The phenylethylamine derivative dopamine (DA) is critically involved in a wide variety of vital functions such as locomotion, feeding, emotions and reward [1-3]. Major DA systems in the brain originate from brainstem DA neurons located in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). SNc neurons project mainly to the caudate/putamen or dorsal striatum (nigrostriatal system), whereas VTA neurons send their axons to the ventral striatum including the nucleus accumbens, as well as certain other limbic (mesolimbic system) and cortical areas (mesocortical system). Small DA-containing cell groups located primarily in the hypothalamus comprise the tuberoinfundibular DA system [4-6]. DA is synthesized from tyrosine by the rate-limiting enzyme tyrosine hydroxylase (TH), to produce L-DOPA which is quickly decarboxylated by L-aromatic acid decarboxylase (L-AADC) to DA [1,3]. Intraneuronal DA is accumulated into synaptic vesicles by the vesicular monoamine transporter-2 (VMAT2) [7,8]. DA released into the extracellular space exerts its physiological functions via activation of G protein-coupled D1-like and D2-like DA receptors [9]. Finally, DA in the extracellular space is subject to dilution by diffusion and metabolic degradation; however the major route of DA clearance from the extracellular space in the striatum/nucleus accumbens is the rapid recycling of the neurotransmitter back into dopaminergic terminals by the Na+/Cl−-dependent plasma membrane dopamine transporter (DAT) [10,11]. Recycled DA in the dopaminergic terminals is then stored in the large intracellular storage pool available for subsequent re-release [12,13].
It is well established that DA neurotransmission in both dorsal and ventral striatum is essential for normal locomotor functions, and progressive degeneration of DA neurons in these areas is a known cause of Parkinson's disease (PD). In most cases. PD becomes clinically apparent when the loss of dopaminergic neurons reaches 60%-70%, which leads to functional dysregulation of the related neuronal circuitry [14-17]. Major motor manifestations of DA deficiency in PD include, but are not limited to, resting tremor (tremor occurring in the absence of voluntary movement), rigidity (tonically increased muscle tone), bradykinesia/akinesia (slowness/difficulty in initiating movement), gait disturbance and postural instability, facial masking, and decreased eyeblinking [18].
Presently, there is no known cure for PD [19,20], however its symptoms can be controlled by therapeutic interventions [21]. DA replacement therapy by administration of the DA precursor, L-DOPA, has been used for many years and remains the gold standard for treatment of PD [22,23]. However, the efficacy of this treatment wanes with time, and fluctuations in motor performance as well as psychotic reactions and dyskinesias often develop. DA agonists, as well as several other classes of drugs directly or indirectly affecting DA function (monoamine oxidase [MAO] inhibitors, COMT [catechol-o-methyl transferase] inhibitors, and amantadine), have some beneficial effects in PD patients, but they are mostly used either at early stages of PD or are applied as adjunct medications to enhance the benefits of L-DOPA [21,24,25]. Due to these limitations of existing therapeutic approaches, the development of better anti-Parkinsonian drugs remains a major objective of PD research.
Several lines of evidence suggest that development of novel non-dopaminergic approaches aimed at bypassing impaired dopaminergic transmission would be beneficial in PD, particularly at later stages [16,26-28], however it is still unclear if these treatments would just potentiate action of residual DA or act completely independently of DA. A number of animal models of DA deficiency, based on pharmacologic, neurotoxic, or genetic approaches, have been developed to understand basic pathological processes leading to PD and/or to search for novel principles of therapy [29-36]. However, in rodents, the prolonged absence of DA is not compatible with life [3,7,8], and animals with chronic severe DA depletion are generally not available for routine experimentation.
We have developed mice lacking the functional DAT (DAT-KO mice) [11] that display remarkable alterations in the compartmentalization of DA [12,13,37]. Lack of the DAT-mediated inward transport in these mice results in an elevated extracellular DA and at least 95% decreased intracellular DA stores. Unlike normal animals, these mice demonstrate remarkable dependence of the remaining DA on ongoing synthesis, and pharmacologic blockade of DA synthesis in DAT-KO mice provides an effective approach to eliminate DA acutely [12,13].
Substituted phenylethylamine derivatives, amphetamines, that are structurally similar to DA and the endogenous trace amine beta-phenylethylamine, represent a well-known group of compounds that potently affect psychomotor functions. Amphetamines are known to interact with plasma membrane monoamine transporters, including DAT, norepinephrine (NE) transporter (NET), and serotonin transporter. This complex interaction results in transporter-dependent efflux of monoamines into extracellular space from intraneuronal stores [10,38,39]. It is commonly believed that DAT-mediated efflux of DA is primarily responsible for the psychostimulant and locomotor actions of these drugs [38,40,41]. Intriguingly, recent studies have identified novel transporter-independent targets of amphetamines. It has been shown that amphetamines, as well as β-phenylethylamine, some monoamine metabolites, and several drugs affecting monoaminergic transmission, can directly activate specific G protein-coupled trace amine (trace amine 1 [TA1]) receptors [42] with currently unknown functional consequences [43,44]. Using DA-depleted DAT-KO mice we observed potent DA-independent antiparkinsonian action of several amphetamine derivatives (17 tested phenylisopropylamines were effective as described below).
The following additional references are noted herein:    Parkes J D et al., Amphetamines in the treatment of Parkinson's disease, J. Neurol Neurosurg Psychiatry 38(3): 232-7 (1975).    Goetz C G et al., Bupropion in Parkinson's disease, Neurology 34(8):1092-4 (1984).    Karoum, F. et al., Metabolism of (−) deprenyl to amphetamine and methamphetamine may be responsible for deprenyl's therapeutic benefit: a biochemical assessment. Neurology. 32(5):503-9 (1982).    Schmidt, W. J. et al., Ecstasy counteracts catalepsy in rats, an anti-parkinsonian effect? Neurosci Lett. 330(3): 251-4 (2002)    M. L. Wadenberg, Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat. Neurosci Biobehav. Rev. 20 325-339 (1996).    Banjaw M Y et al., Anticataleptic activity of cathinone and MDMA (Ecstasy) upon acute and subchronic administration in rat. Synapse 49(4):232-8 (2003)    Fuller, R. W., Fenfluramine and Parkinson's disease, Arch Neurol. 34(11):720 (1977)
Beasley B L et al., Fenfluramine hydrochloride treatment of parkinsonism, Arch Neurol. 34(4):255-6 (1977)(negative study)
Dawirs, R., Use of NeuroactiveSubstances for the Treatment of Parkinson's Disease and Pharmaceutical Combination, US Pat. Application 2004/0147613.